The overall objective of this project is to define the role of chloride in the regulation of renin secretion. In the NaCl-deprived rat, renin release was inhibited by acute intravenous infusion of NaCl, NaBr, and lysine monohydrochloride; renin was not inhibited by NaHCO3, NaNO3, or lysine glutamate. During infusion with sodium salts that suppressed renin, negative free water clearance increased. Selective chloride depletion produced in the rat by peritoneal dialysis against NaHCO3 or NaNO3 stimulated renin release, whereas dialysis against NaCl did not. Free water excretion was lower in chloride depleted animals. In the dog, renin release as inhibited by infusion of HCl but not H2SO4, despite comparable acidosis, indicating that acidosis per se does not effect renin secretion. Taken together, these results suggest that the macula densa mechanism for renin release is specifically related to chloride transport. In potassium depleted rats, plasma renin was increased and renin secretion was not suppressed by acute intravenous infusion of sodium chloride, suggesting that potassium depletion stimulates renin release by altering the chloride signal at the macula densa.